Process for preparing 3-methylsulfonylpropionitrile

ABSTRACT

The present invention relates to processes for preparing 3-methylsulfonylpropionitrile. The processes provide a good yield and a good purity of the final product and provide a controllable reaction. The present invention also relates to a crystalline form of 3-methylsulfonylpropionitrile having X-ray diffraction peaks at 13.9±0.1, 19.2±0.1, 20.0±0.1, 22.5±0.1, 23.2±0.1, 25.7±0.1, 28.1±0.1, 29.9±0.1, and 30.6±0.1 degrees 2θ, and wherein the most intense peak is the peak at 13.9±0.1 degrees 2θ.

This application claims the benefit of U.S. Provisional Application No.61/603,744, filed Feb. 27, 2012; which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes for preparing3-methylsulfonylpropionitrile. The present invention also relates to acrystalline form of 3-methylsulfonylpropionitrile.

BACKGROUND OF THE INVENTION

3-Methylsulfonylpropionitrile (CAS Registry 54863-37-5) is useful fortreating inflammation and pain as described in U.S. Publication No.2012-0157524, which is incorporated herein by reference in its entirety.

There is a need for efficient processes for preparing the3-methylsulfonylpropionitrile, particularly in a large scale of over 1Kg.

SUMMARY OF THE INVENTION

The present invention is directed to methods for preparing3-methylsulfonylpropionitrile. In one method, the method comprises thesteps of: (a) reacting 3-bromopropionitrile and sodium methylsulfinatein an organic solvent to obtain crude 3-methylsulfonylpropionitrile in asolid form, and (b) removing a byproduct sodium bromide.

In an alternative method, the method comprises the steps of: (a)reacting 3-bromopropionitrile and sodium thiomethoxide in a firstaqueous solution to form methylthiopropionitrile, (b) separating thereaction mixture of (a) into an aqueous phase and an organic phase andcollecting the organic phase, (c) isolating methylthiopropionitrile inthe organic phase, (d) mixing the isolated methylthiopropionitrile withacetic anhydride, (e) reacting the mixture of (d) with a second aqueoussolution comprising acetic acid, acetic anhydride and hydrogen peroxideat 25-42° C. to form 3-methylthiopropionitrile, and (f) isolating3-methylsulfonylpropionitrile from the reaction mixture of (e).

The present invention is further directed to a crystalline form of3-methylsulfonylpropionitrile having X-ray diffraction peaks at13.9±0.1, 19.2±0.1, 20.0±0.1, 22.5±0.1, 23.2±0.1, 25.7±0.1, 28.1±0.1,29.9±0.1, and 30.6±0.1 degrees 2θ, and wherein the most intense peak isthe peak at 13.9±0.1 degrees 2θ.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A-1C illustrate a flow chart for preparing3-methylsulfonylpropionitrile according to Example 1.

FIG. 2A-2D show the X-ray diffraction spectra of3-methylsulfonylpropionitrile recrystallized in ethanol, chloroform,toluene, and ethyl acetate, respectively.

FIG. 3A-3B illustrate a flow chart for preparing3-methylsulfonylpropionitrile according to Example 4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to processes for preparing purifiedcompound of 3-methylsulfonylpropionitrile:

The process of the present invention is either a one-step reaction ortwo-step reactions. The process is suitable for large-scale production(over 1 Kg, preferably over 2 Kg, over 4 Kg, or over 10 Kg). The processprovides good yield of ≧75%, preferably ≧80%, or ≧85%. The processprovides purity of 3-methylsulfonylpropionitrile ≧80%, preferably ≧85%,or ≧90%, or ≧95%, or ≧98%.

One-Step Reaction

The present invention is directed to a method for preparing3-methylsulfonylpropionitrile. The method comprises the steps of:

(a) reacting 3-bromopropionitrile (BPN) and sodium methylsulfinate in anorganic solvent to obtain crude 3-methylsulfonylpropionitrile in a solidform, and

(b) removing a byproduct sodium bromide.

The method optionally comprises a step (c) after step (b):

(c) purifying 3-methylsulfonylpropionitrile.

In step (a), the crude 3-methylsulfonylpropionitrile is prepared via aone-step synthetic route involving alkylation of methanesulfinic acidsodium salt with 3-bromopropionitrile.

An organic solvent is used in the reaction to facilitate the alkylationand enable isolation of a crude product filter cake (mixture of3-methylprpionitrile and sodium bromide NaBr). Examples of suitableorganic solvents include ethanol, methanol, propanol, isopropanol,butanol, or a mixture thereof. Preferred organic solvent is ethanol, ora mixture of alcoholic solvents containing ethanol (e.g.,ethanol/methanol/isopropanol at 90/5/5).

In general, 3-bromopropionitrile is utilized in a molar excess oversodium methylsulfinate to avoid the isolation of a final product from animpurity associated with the sodium methylsulfinate starting material.For example, 3-bromopropionitrile is typically in 10-30% molar excess(e.g., 20% molar excess) over methylsulfinate.

In general, the reaction is carried at a temperature higher than ambienttemperature to accelerate the reaction rate. Preferably, the reaction iscarried at ≧40° C., or ≧50° C., or ≧60° C., or ≧70° C. For example, whenethanol is used as the solvent medium, the reaction temperature is ingeneral 74-83° C., preferably 75-81° C.

The reaction time should be sufficient to allow the reaction to go tocompletion. In general, the reaction time is at least 8 hours, forexample, 8-48 hours, preferably 14-20 hours, or 16-18 hours. Uponcompletion of the reaction, the reaction mixture contains a mixture ofsolids: the product 3-methylsulfonylpropionitrile, NaBr and residualBPN.

After the reaction, the crude 3-methylsulfonylpropionitrile is obtainedin a solid form from the reaction mixture. In one embodiment, thereaction mixture is cooled to ≦15° C. (preferably ≦10° C., or 1-9° C.)to increase the precipitation of 3-methylsulfonylpropionitrile from thereaction mixture. The cooling period is preferably over 1 hour, or 2hours. The reaction mixture is then filtered and the crude3-methylsulfonylpropionitrile is in a form of damp filter cake, whichalso contains NaBr and trace residual BPN. Most of the excess BPN isremoved by filtration and appears in the filtrate. The damp filter cakeis optionally washed with the same organic solvent and dried undervacuum.

In step (b), the byproduct sodium bromide is removed by (i) addingacetone to the filter cake to dissolve the solid and form a solution,(ii) filtering the solution to remove an insoluble byproduct, and (iii)collecting the filtrate. 3-methylsulfonylpropionitrile is soluble inacetone, whereas the byproduct sodium bromide is insoluble in acetone.After filtration, the insoluble sodium bromide is removed from theacetone filtrate that contains the product 3-methylsulfonylpropionitrileand trace BPN. Other solvents in which the product is soluble but NaBris not (e.g., tetrahydrofuran or dichloromethane) may be used instead ofacetone. However, acetone is a preferred solvent because of the relativehigh solubility of the product in acetone. In addition, acetone does notform an oxidation byproduct, and it is easy to be removed.

In the optional step (c), 3-methylsulfonylpropionitrile is furtherpurified to remove trace BPN in the acetone filtrate, by concentratingthe acetone filtrate, dissolving the dried material in a suitableorganic solvent, and crystallizing 3-methylsulfonylpropionitrile.

In one embodiment, the product-rich filtrates are concentrated todryness via vacuum distillation and then dissolved in an organic solventsuitable for crystallization of the product.

In another embodiment, the acetone in the acetone filtrate is replacedwith an organic solvent having a higher boiling temperature than acetoneand in which the product is soluble, by heating the acetone filtrate andadding the organic solvent in increments. For example, the acetonefiltrate is transferred to a large jacketed reactor and acetone isremoved under reduced pressure while heating with the concomitantaddition of ethanol. At the end of this step, the reactor contains a hotethanolic solution of product and trace residual BPN. As the hotethanolic solution cools, crystalline product begins to precipitate. Themixture is further cooled, for example, to ≦10° C., to complete theprecipitation process. The crystalline product is essentially devoid ofresidual BPN (<0.02%), which remains in the liquid and is removed by thecrystallization step.

Two-Step Reactions

The process comprises the steps of: (a) reacting bromopropionitrile andsodium thiomethoxide (NaSMe) in a first aqueous solution to formmethylthiopropionitrile, (b) separating the reaction mixture of (a) intoan aqueous phase and an organic phase, (c) isolatingmethylthiopropionitrile in the organic phase, (d) mixing the isolatedmethylthiopropionitrile with acetic anhydride, (e) reacting the mixtureof (d) with a second aqueous solution comprising acetic acid, aceticanhydride and hydrogen peroxide at 25-42° C. to formmethylsulfonylpropionitrile, and (f) isolatingmethylsulfonylpropionitrile from the reaction mixture of (e).

The inventors have discovered that by reacting bromopropionitrile andsodium thiomethoxide in an aqueous solution, the intermediatemethylthiopropionitrile formed can be easily separated from otherreagents. The inventors also discovered that the two-step oxidation ofthe intermediate methylthiopropionitrile (steps (d) and (e)) in atemperature 25-42° C. provides a controlled reaction and a good yield ofthe final product.

The reaction step (a) is an alkylation step, which reactsbromopropionitrile and sodium thiomethoxide (NaSMe) in an aqueoussolution to form an intermediate methylthiopropionitrile.

The alkylation reaction is typically carried out at 10-25° C.,preferably 10-20° C. The reaction time is 1-4 hours, preferably 2-3hours. In one embodiment, liquid 3-bromoproprionitrile is added to anaqueous solution of sodium thiomethoxide (e.g., 14-21% w/w). Thealkylation is carried out in an aqueous solution instead of an organicsolvent such as an alcohol. The aqueous solution facilitates an easyisolation of the intermediate methylthiopropionitrile (MTPN) from otherreagents that remain in the aqueous phase. 3-bromoproprionitrile is usedin the alkylation reaction instead of 3-chloroproprionitrile because (a)Br is more reactive toward substitution than Cl, and (b) Br reagent(HMIS health hazard rating=2) is less hazardous than Cl reagent (HMIShealth hazard rating=4).

After the alkylation step, the reaction mixture is allowed to settle andto separate into two phases: a lower aqueous phase and an upper organicphase containing MTPN. MTPN, which is less dense than water, accumulatesin a layer above the surface of the water. Excess methylthiomethoxideand sodium bromide byproduct remain in the aqueous phase. The loweraqueous layer is discarded, and the upper organic phase of MTPN isobtained. The organic phase is optionally dried over solid sodiumsulfate to remove residual water and water soluble salts. The dried MTPNis isolated (for example, by vacuum filtration) as a clear oily liquid.

The intermediate MTPN is then oxidized to form the final product of3-methylsulfonylproprionitrile.

The inventors discovered that one-pot oxidation of MTPN to sulfoxide(—SO—) and subsequent sulfone (—SO₂—) in acetic acid, acetic anhydride,and hydrogen peroxide solution, as shown below, was extremely difficultto control in the scale of hundred grams.

An induction period was noticed before the initiation of the secondoxidation (sulfoxide to the sulfone). At this point, heat evolutionceased and the pot temperature rapidly decreased. After warming thereactor gently to induce oxidation, the temperature steadily increaseddue to the exothermic oxidation, even though the jacket recirculator wasat maximum cooling capacity. The evolution of heat continued to increaseand the reaction temperature was not controllable.

To remedy this situation, the inventors have discovered two-stepprocedures, by which the reaction is controlled and the yield of thefinal product is improved. In the present invention, the oxidation iscarried out by two steps: (d) mixing MTPN with acetic anhydride, and (e)reacting the mixture of (d) with an aqueous solution comprising aceticacid, acetic anhydride and hydrogen peroxide at 25-42° C. to form thefinal product 3-methylsulfonylpropionitrile (MSPN). The reaction time isin general 1-4 hours, preferably 1-3 hours, or 1-2 hours In oneembodiment, the MTPN is mixed with acetic anhydride at a molar ratio of1:1-3, preferably about 1:2, and then slowly added to the reactorcontaining acetic acid, acetic anhydride and aqueous hydrogen peroxide(e.g., 20-40% w/v) while maintaining the temperature at 25-42° C.,preferably 28-40° C., and more preferably 30-35° C. The two-stepprocedures eliminate the induction period and allow the reactiontemperature to be controlled.

After the oxidation reaction is completed, the final product MSPN isisolated from the reaction mixture by removing acetic acid and residualhydrogen peroxide. In one embodiment, the acetic acid and residualhydrogen peroxide are removed by distillation and/or rotary evaporation.After concentration, the product is mixed with ethanol, heated and thencooled to 5-10° C. to effect crystallization. The product can beisolated by vacuum filtration and washed with cold ethanol. The typicalyield of the crystalline MSPN material from the oxidation of theintermediate MTPN is about 90%. The typical overall yield of thecrystalline MSPN material from the starting materials is about 76-80%.

Crystalline Form

3-Methylsulfonylpropionitrile is recrystallized using solvents ofvarying polarity to determine if the material exhibits multiplemorphologies when recrystallized from various solvents. Afterre-crystallized in ethanol, chloroform, toluene, and ethyl acetate, thecrystalline materials are analyzed by X-ray diffraction (XRD) todetermine differences in interplanar or lattice spacing (d-spacing) anddiffraction patterns. All of the crystalline samples contain the samediffraction peaks except in varying intensities.

The present invention is directed to a crystalline form of3-methylsulfonylpropionitrile having X-ray diffraction peaks at13.9±0.1, 19.2±0.1, 20.0±0.1, 22.5±0.1, 23.2±0.1, 25.7±0.1, 28.1±0.1,29.9±0.1, and 30.6±0.1 degrees 2θ, and wherein the most intense peak isthe peak at 13.9±0.1 degrees 2θ.

The present invention provides pharmaceutical compositions comprisingone or more pharmaceutically acceptable carriers and the crystallineform of 3-methanesulfonylpropionitrile, or a pharmaceutically acceptablesalt, or solvate thereof. The active compound3-methanesulfonylpropionitrile, or its pharmaceutically acceptable saltor solvate in the pharmaceutical compositions in general is in an amountof about 0.01-20%, or 0.05-20%, or 0.1-20%, or 0.2-15%, or 0.5-10%, or1-5% (w/w) for a topical formulation; about 0.1-5% for an injectableformulation, 0.1-5% for a patch formulation, about 1-90% for a tabletformulation, and 1-100% for a capsule formulation.

The present invention provides a method of treating inflammation and/orpain. The active compound 3-methanesulfonylpropionitrile in acrystalline form can be used as is, or it can be administered in theform of a pharmaceutical composition that additionally contains apharmaceutically acceptable carrier. The method comprise the steps offirst identifying a subject suffering from inflammation and/or pain, andadministering to the subject 3-methanesulfonylpropionitrile, in anamount effective to treat inflammation and/or pain. “An effectiveamount,” as used herein, is the amount effective to treat a disease byameliorating the pathological condition or reducing the symptoms of thedisease.

The pharmaceutical compositions comprising3-methanesulfonylpropionitrile and the method of treating inflammationand/or pain by administering 3-methanesulfonylpropionitrile have beendescribed in details in co-pending application Ser. No. 13/324,777,which is incorporated herein by reference in its entirety.

The following examples further illustrate the present invention. Theseexamples are intended merely to be illustrative of the present inventionand are not to be construed as being limiting.

EXAMPLES Example 1 Preparation of 3-Methylsulfonylpropionitrile(Two-Step Reactions)

FIG. 1A-1C illustrate the process of Example 1.

a. Alkylation of Sodium Thiomethoxide by 3-Bromopropionitrile

1 L (˜1110 g) of a 21% aqueous solution of sodium thiomethoxide (3.33mol, obtained from Sigma-Aldrich) was added to a 2 L 3-neck round bottomflask equipped with mechanical stirrer and thermometer. The solution wascooled to 16±2° C. using an ice bath and 403.7 g (3.00 mol) of3-bromopropionitrile (Sigma-Aldrich) was slowly added under moderateagitation over ˜1 hr while maintaining the pot temperature at ≦20° C.throughout the addition. Stirring was continued for ˜1½ hr at roomtemperature, and then the contents were transferred to a 2 L separatoryfunnel and allowed the resulting two-phase system to settle for ˜15minutes. The lower aqueous layer was discarded and the upper organiclayer was transferred to a 500 mL beaker containing 60 g anhydroussodium sulfate and stirred for ˜1 hr. The dried methylthiopropionitrilewas isolated by vacuum filtration to yield 279 g (2.75 mol) of a clearoily liquid.

b. Oxidation of Intermediate Methylthiopropionitrile (MTPN)

1 L acetic acid (17.4 mol), 500 mL acetic anhydride (5.30 mol) and 1 L30% aqueous hydrogen peroxide (9.77 mol) were added to a 5 L jacketedreactor equipped with a mechanical stirrer, Julabo FP50-HL recirculator(set in external control mode) fitted with a Julabo PT100 remotetemperature sensor inserted into one of the reactor lid ports to recordand control the pot temperature. The reactor contents were slowly heatedto 30-32° C. under moderate agitation. While the reactor was heating,the oil liquid methylthiopropionitrile obtained from (a) was mixed with500 mL (5.30 mol) acetic anhydride, transferred to an addition funneland fitted into one of the reactor lid ports. When the pot temperaturestabilized at 30-32° C., the methylhtiopropionitrile/acetic anhydridesolution was slowly added to the reactor over 1½-2 hr while maintaininga pot temperature of 30-34° C. Upon completion of themethylthiopropionitrile addition, the addition funnel was rinsed with 50mL acetic anhydride and the reactor was then stirred for 10 minutes at32±2° C. The reaction mixture (˜3.5 L) was then transferred to a 10 LBüchi distillation flask and concentrated on a Büchi R220 rotaryevaporation unit at 50-60° C., 20 mbar (15 mmHg) and rotation ˜90 rpmuntil the bulk of the acetic acid with residual peroxide was distilled.

The material remaining in the 10 L distillation flask (˜500-600 mL) wastransferred to a 2 L 1-neck round bottom flask and concentrated to˜300-400 mL on a Büchi R124 rotary evaporator at 50-60° C. and 1 mmHg.The concentrate was added to the 5 L jacketed reactor with 2.7 L ethanolheated to 60-65° C. under moderate agitation. The mixture was slowlycooled to 5-10° C. over ˜1½ hr to effect crystallization, stirred ˜½ hrat 5-10° C. and isolated by vacuum filtration.

c. Recrystallization of Product 3-Methylsulfonylpropionitrile (MSPN)

The damp filter cake is added to a 5 L reactor with 2.7 L ethanol. Theslurry was heated to 60-65° C. under moderate agitation and held untiltotal dissolution (˜5-10 min). The solution was slowly cooled to 5-10°C. over ˜1½ hr to effect crystallization, stirred ½ hr at 5-10° C. andisolated by vacuum filtration. The isolated product was dried in vacuoat 30-35° C. to yield 310 g (2.33 mol, 78% yield from3-bromopropionitrile) of a white crystalline material.

Example 2 Crystalline Form of 3-Methylsulfonylpropionitrile

3-Methylsulfonylpropionitrile (MSPN) was recrystallized from varioussolvents, e.g., ethanol, ethyl acetate, chloroform, and toluene.

MSPN recrystallized from ethanol was obtained from Example 1. Therecrystallized

MSPN was dissolved by warming it to 65±2° C. in ethyl acetate (200mg/mL), chloroform (200 mg/mL), and toluene (about 35 mg/mL). Oncedissolved, the samples were allowed to equilibrate at room temperature(about 20° C.) for about 1 hour at which point crystals were observed inall three of the samples. The samples were then held in −20° C. storage,to maximize yield, and filtered the following day. The filtered sampleswere dried in vacuo at room temperature for about 1½ hr before beingpackaged and sent for XRD analysis.

To measure the diffraction pattern of crystal structures, the planedistance of the crystals and the intensity of diffraction rays, powderX-ray diffraction analysis was carried out. FIG. 2A-2D show the X-raydiffraction spectra of 3-methylsulfonylpropionitrile recrystallized inethanol, chloroform, toluene, and ethyl acetate, respectively.

Characteristic peaks appearing in the X-ray diffraction spectra of MSPNrecrystallized in ethanol, chloroform, toluene, and ethyl acetate, areshown in Table 1, wherein “2θ” represents diffraction angle, “d”represents the distance between crystal planes. The analysis was carriedout using ARL X' TRA Powder Diffractometer (Thermo Fisher).

TABLE 1 XRD Data Summary Area ratio to primary 2Θ value 2-Θ d(Å) Ethyl(±0.05) (±0.01) Ethanol Chloroform Toluene Acetate 13.94 6.34 100.0% 100.0%  100.0%  100.0%  19.22 4.61 3.9% 2.5% 6.3% 36.7% 20.04 4.43 4.5%2.5% 5.8% 45.1% 22.46 3.96 4.8% 3.2% 6.2% 46.1% 23.18 3.83 7.6% 4.7%10.8%  71.5% 25.66 3.47 1.4% 0.5% 0.7%  3.7% 28.08 3.17 3.8% 4.4% 4.4% 2.9% 29.86 2.99 15.2%  15.2%  16.1%  51.7% 30.58 2.92 0.3% 0.6% 1.0% 7.7%

The XRD data show that MSPN recrystallized in ethanol, chloroform, andtoluene exhibited almost identical diffraction patterns with primary 2θvalues of 13.94 (100%) and 29.86 (15.2-16.1%). The MSPN recrystallizedfrom ethyl acetate exhibited a more diverse pattern; although it alsohad 2θ 13.935 as the most intense peak, it had different intensities ofseveral other peaks when comparing with other re-crystallized form.Table 1 showed that all of samples contained the same diffraction peaksexcept in varying intensities.

The ethyl acetate recrystallized MSPN was further evaluated to determineif solvation could be attributable to the variation in peak intensities.Analysis for residual solvents by Gas Chromatography equipped with Flameionization detection using standard methodology (e.g.USP method <467>)indicated 4100 ppm (0.41%) ethyl acetate (about 160:1 mole ratio MSPN tosolvent), which suggests that the difference in peak intensities of thediffraction pattern is not likely due to solvation. The ethyl acetaterecrystallized MSPN and the ethanol recrystallized MSPN were furtherdried (in vacuo at 35° C., 16 hr) and resulted in 0.53% LOD (loss ondrying) and 0.42% LOD respectively. These samples were reanalyzed by XRDto determine the impact on crystal structures. The spectra indicate thatadditional drying had no impact on the diffraction pattern of thesematerials.

Example 3 Preparation of 3-Methylsulfonylpropionitrile (One-StepReaction)

1818.3 g sodium methylsulfinate (Oakwood Products, Inc., product# 1284,16.5 mol) and 12.5 L ethanol (Pharmco-Aaper, Product # 241000200) wereadded to a 20 L jacketed reactor equipped with a mechanical stirrer withtachometer, Julabo FP50-HL recirculator fitted with a Julabo PT100remote temperature sensor inserted into one of the reactor lid ports torecord and control the pot temperature and a condenser equipped with arecirculating chiller. The slurry was mixed under moderate agitation andthe Julabo was set to heat the batch to 78±3° C. in external (batch)control mode. The addition of 2652.9 g (19.7 mol) 3-bromopropionitrile(Far Chemical, Inc.) was conducted as the batch was heating. Thecontents of the reactor were held at 79±2° C. for 16 hours. The reactorwas slowly cooled from 79° C. to 5° C. over a two-hour period. The batchwas held for ˜30 minutes at 5±5° C. prior to isolation by vacuumfiltration. The filter cake was washed with 2.0 L ethanol and allowed tohold under vacuum ˜30 minutes prior to removal of the solids from thefilter and collection of 4113.6 g damp filter cake.

15.0 L acetone was added to the 20 L jacketed and heated to 21±3° C.under moderate agitation. The damp filter cake was added to the reactorand allowed to mix for 1 hour. The insoluble salts were isolated byvacuum filtration and the filter cake was washed with 2.0 L acetone. Thefiltrate (˜15 L) was slowly added to a 20 L Büchi distillation flaskattached to a Bü{umlaut over (c)}{umlaut over (h)}ï R220 rotaryevaporation unit at 50-60° C., 200 mbar (150 mmHg) and rotation ˜90 rpm.The filtrate was gradually added as the distillation of acetonecommenced and the distillation flask was concentrated to dryness over˜3-4 hours.

During the distillation step, the 20 L reactor was cleaned, charged with17.3 L ethanol and heated to 65-70° C. under moderate agitation. Theconcentrated solids were scraped from the 20 L distillation flask andadded to the hot ethanol in the 20 L reactor. The reactor was cooled to55±4° C. to effect crystallization. The mixture was slowly cooled to5-10° C. over ˜1½ hr to affect crystallization, stirred ˜½ hr at 5±4° C.and isolated by vacuum filtration. The damp filter cake was washed with2.0 L ethanol. The isolated product was dried in vacuo at 30-35° C. toyield 1931.2 g (14.5 mol, 88% yield from sodium methylsulfinate) of awhite crystalline material.

Example 4 Preparation of 3-Methylsulfonylpropionitrile, AlternativeProcedures (One-Step Reaction)

FIG. 3A-3B illustrate the process of Example 4.

Sodium methylsulfinate and ethanol are added to a 50 L jacketed reactorand the batch is heated to 78±3° C. The addition of bromopropionitrileis conducted as the batch is heating. The reactor contents are held at79±2° C. for 16 hours. The reactor is slowly cooled, by programming thetemperature control system, from 79° C. to 5° C. over a two-hour period.The batch is held for about 30 minutes at 5±5° C. prior to isolation byvacuum filtration. The filter cake is washed with ethanol and allowed tohold under vacuum for about 30 minutes prior to removal of the crudesolid from the filter.

Acetone is added to the 50 L jacketed reactor and heated to roomtemperature (21±4° C.) under moderate agitation. The damp filter cake isadded to the reactor and allowed to mix for 1 hour. The insoluble salts(sodium bromide) are isolated by vacuum filtration and the filter cakeis washed with acetone. The acetone filtrates (product solution) areadded to a second 50 L jacketed reactor configured as a distillationvessel. The distillation reactor is heated to 60±5° C. and acetonedistillate is collected in the distillate receiver. The contents of thedistillation reactor are concentrated to approximately half of theinitial volume. Ethanol is added in increments to maintain the reactorat approximately half volume while maintaining a temperature controllerset point of 5-15° C. above the pot temperature. The displacement ofacetone with ethanol is continued until the pot temperature levels offat 76-80° C. Ethanol is added to bring the reactor to full volume. Thereactor is slowly cooled, by programming the temperature control system,from 79° C. to 5° C. over a two hour period. The batch is held for ˜30minutes at 5±5° C. prior to isolation. The product is isolated by vacuumfiltration and washed with ethanol.

The invention, and the manner and process of making and using it, arenow described in such full, clear, concise and exact terms as to enableany person skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the scope of the present invention as setforth in the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thespecification.

What is claimed is:
 1. A method for preparing3-methylsulfonylpropionitrile, comprising: (a) reacting3-bromopropionitrile and sodium methylsulfinate in an organic solvent toobtain crude 3-methylsulfonylpropionitrile in a solid form, and (b)removing a byproduct sodium bromide.
 2. The method according to claim 1,further comprising a step (c) after step (b): (c) purifying3-methylsulfonylpropionitrile.
 3. The method according to claim 1,wherein the step (a) comprises: (i) reacting 3-bromopropionitrile andsodium methylsulfinate in the organic solvent at ≧40° C. for at least 8hours, and (ii) cooling the reaction mixture to ≦15° C., and (iii)isolating 3-methylthiopropionitrile in the solid form from the cooledreaction mixture.
 4. The method according to claim 1, wherein theorganic solvent comprises ethanol, methanol, propanol, isopropanol,butanol, or a mixture thereof.
 5. The method according to claim 4,wherein the organic solvent comprises ethanol.
 6. The method accordingto claim 1, wherein 3-bromopropionitrile and sodium methylsulfinate arereacted in an ethanol solvent at 75-83° C.
 7. The method according toclaim 1, wherein the byproduct is removed by: (i) adding acetone to thesolid form of the step (a) to dissolve the solid and form a solution,(ii) filtering the solution of (i) to remove the insoluble byproduct,and (iii) collecting the filtrate.
 8. The method according to claim 7,wherein 3-methylsulfonylpropionitrile is purified by drying the filtrateof (iii), dissolving the dried material in a second organic solvent, andcrystallizing 3-methylsulfonylpropionitrile.
 9. The method according toclaim 8, wherein the second organic solvent is selected from the groupconsisting of ethanol, methanol, propanol, isopropanol, butanol,ethylacetate, or a mixture thereof.
 10. The method according to claim 9,wherein the second organic solvent is ethanol.